Novel Polymorphs Of Azabicyclohexane

Abstract

The invention provides polymorphic crystalline forms of acid addition salts of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane designated as polymorph form A, polymorph form B and polymorph form C, where polymorph form A is more thermodynamically stable than the other forms, methods for preparing and using such polymorph forms and pharmaceutical compositions containing such polymorph forms.

1 . A polymorph of an acid addition salt of (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof. 
     
     
         2 . The acid addition salt of  claim 1  wherein said salt is a hydrochloride salt. 
     
     
         3 . The polymorph form A of an acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof. 
     
     
         4 . The polymorph form A of  claim 3  wherein said acid addition salt is a hydrochloride salt. 
     
     
         5 . The polymorph form A of  claim 4  wherein the X-ray powder diffraction pattern of said polymorph, as measured at crystal sizes of from about 10 to 40 microns, is characterized by peaks at one or more of and at about the following °2θ (degree) values:
 17.14; 
 19.62; 
 21.96; 
 24.52;
 and 
 
 26.74. 
 
     
     
         6 . The polymorph form A of  claim 4  wherein the X-ray powder diffraction pattern of said polymorph, as measured at crystal sizes of from about 10 to 40 microns, is characterized by peaks at all of and at about the following °2θ (degree) values:
 17.14; 
 19.62; 
 21.96; 
 24.52;
 and 
 
 26.74. 
 
     
     
         7 . The polymorph form A of  claim 4  wherein Raman spectrum of said polymorph is characterized by peaks at one or more of and at about the following wavenumbers (cm −1 ):
 762; 
 836; 
 921; 
 959; 
 1393; 
 1597; 
 2890; 
 2982;
 and 
 
 3064. 
 
     
     
         8 . The polymorph form A of  claim 4  wherein the Raman spectrum of said polymorph is characterized by peaks at all of and at about the following wavenumbers (cm −1 ):
 762; 
 836; 
 921; 
 959; 
 1393; 
 1597; 
 2890; 
 2982;
 and 
 
 3064. 
 
     
     
         9 . The polymorph form B of an acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof. 
     
     
         10 . The polymorph form B of  claim 9  wherein said acid addition salt is a hydrochloride salt. 
     
     
         11 . The polymorph form B of  claim 10  wherein the X-ray powder diffraction pattern of said polymorph, as measured at crystal sizes of from about 10 to 40 microns, is characterized by peaks at one or more of and at about the following °2θ (degree) values:
 15.58; 
 17.52; 
 21.35; 
 23.04; 
 25.43;
 and 
 
 30.72. 
 
     
     
         12 . The polymorph form B of  claim 10  wherein the X-ray powder diffraction pattern of said polymorph, as measured at crystal sizes of from about 10 to 40 microns, is characterized by peaks at all of and at about the following °2θ (degree) values:
 15.58; 
 17.52; 
 21.35; 
 23.04; 
 25.43; 
 and 30.72. 
 
     
     
         13 . The polymorph form B of  claim 10  wherein the Raman spectrum of said polymorph is characterized by peaks at one or more of and at about the following wavenumbers (cm −1 ):
 1245; 
 1380; 
 2963; 
 2993; 
 3027;
 and 
 
 3066. 
 
     
     
         14 . The polymorph form B of  claim 10  wherein the Raman spectrum of said polymorph is characterized by peaks at all of and at about the following wavenumbers (cm −1 ):
 1245; 
 1380; 
 2963; 
 2993; 
 3027;
 and 
 
 3066. 
 
     
     
         15 . The polymorph form C of an acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof. 
     
     
         16 . The polymorph form C of  claim 15  wherein said acid addition salt is a hydrochloride salt. 
     
     
         17 . The polymorph form C of  claim 16  wherein the X-ray powder diffraction pattern of said polymorph, as measured at crystal sizes of from about 10 to 40 microns, is characterized by peaks at one or more of and at about the following °2θ (degree) values:
 13.34; 
 17.64; 
 20.07; 
 21.32; 
 22.97; 
 24.86; 
 26.32;
 and 
 
 27.90. 
 
     
     
         18 . The polymorph form C of  claim 16  wherein the X-ray powder diffraction pattern of said polymorph, as measured at crystal sizes of from about 10 to 40 microns, is characterized by peaks at all of and at about the following °2θ (degree) values:
 13.34; 
 17.64; 
 20.07; 
 21.32; 
 22.97; 
 24.86; 
 26.32;
 and 
 
 27.90. 
 
     
     
         19 . The polymorph form C of  claim 16  wherein the Raman spectrum of said polymorph is characterized by peaks at one or more of and at about the following wavenumbers (cm −1 ):
 1059; 
 1094; 
 1266; 
 1343; 
 1595; 
 2966; 
 2900;
 and 
 
 3070. 
 
     
     
         20 . The polymorph form C of  claim 16  wherein the Raman spectrum of said polymorph is characterized by peaks at all of and at about the following wavenumbers (cm −1 ):
 1059; 
 1094; 
 1266; 
 1343; 
 1595; 
 2966; 
 2900;
 and 
 
 3070. 
 
     
     
         21 . A method of producing polymorph form A of an acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof comprising dissolving a solid containing one or more polymorphs of the acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] other than polymorph form A in a solvent medium containing water and allowing said solvent medium to evaporate at a temperature of from about 15° C. to 35° C. while exposed to the atmosphere to remove said solvent medium and produce said polymorph form A in crystalline form. 
     
     
         22 . The method of  claim 21  wherein said solid is a mixture of polymorph forms A and B of an acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. 
     
     
         23 . The method of  claim 22  wherein said acid addition salt is a hydrochloride salt. 
     
     
         24 . The method of  claim 21  wherein said solvent medium contains a lower alkanol. 
     
     
         25 . The method of  claim 21  wherein the evaporation takes place over a period of at least 4 hours until said solvent medium evaporates. 
     
     
         26 . The polymorph form A in crystalline form produced in accordance with the method of  claim 21 . 
     
     
         27 . A method of producing polymorph form B of an acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof comprising dissolving a solid containing one or more polymorphs of the acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] other than polymorph form B in an anhydrous organic solvent and crystallizing from said solvent under anhydrous conditions at temperatures of from about 50° C. to 85° C. said polymorph form B in crystalline form. 
     
     
         28 . The method of  claim 27  wherein said acid addition salt is a hydrochloride salt. 
     
     
         29 . The method of  claim 27  wherein said solid is a mixture of polymorph forms A and B of an acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. 
     
     
         30 . The polymorph form B in crystalline form produced in accordance with the method of  claim 27 . 
     
     
         31 . A method of producing polymorph form C of an acid addition salt of (+)-1-(3,4-dichlorophenyl)-3azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof comprising heating a solid containing one or more polymorphs of the acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane other than polymorph form C to a temperature of at least 50° C. until said polymorph form C in crystalline form is produced. 
     
     
         32 . The method of  claim 31  wherein said acid addition salt is a hydrochloride salt. 
     
     
         33 . The method of  claim 31  wherein said solid is a mixture of polymorph forms A and B of an acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. 
     
     
         34 . The method of  claim 31  wherein said solid is a mixture of polymorph forms A, B and C of an acid addition salt of (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. 
     
     
         35 . The polymorph form C in crystalline form produced in accordance with the method of  claim 31 . 
     
     
         36 . A pharmaceutical composition in oral unit dosage form comprising solid polymorph form A of a pharmaceutically acceptable acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof and an inert pharmaceutically acceptable carrier or diluent. 
     
     
         37 . The pharmaceutical composition of  claim 36  wherein said pharmaceutically acceptable acid addition salt is a hydrochloride salt. 
     
     
         38 . The oral unit dosage form of  claim 37  wherein said polymorph form A in crystalline form is present in said oral unit dosage form in the amount of about 25 mg to about 300 mg. 
     
     
         39 . The pharmaceutical composition of  claim 38  wherein said oral unit dosage form is a tablet or capsule. 
     
     
         40 . A pharmaceutical composition in oral unit dosage form comprising solid polymorph form B of a pharmaceutically acceptable acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof and an inert pharmaceutically acceptable carrier or diluent. 
     
     
         41 . The pharmaceutical composition of  claim 40  wherein said pharmaceutically acceptable acid addition salt is a hydrochloride salt. 
     
     
         42 . The oral unit dosage form of  claim 41  wherein said polymorph form B in crystalline form is present in said oral unit dosage form in the amount of about 50 mg to about 200 mg. 
     
     
         43 . The pharmaceutical composition of  claim 42  wherein said oral dosage form is a tablet or capsule. 
     
     
         44 . A pharmaceutical composition in oral unit dosage form comprising solid polymorph form C of a pharmaceutically acceptable acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof and an inert pharmaceutically acceptable carrier or diluent. 
     
     
         45 . The pharmaceutical composition of  claim 44  wherein said pharmaceutically acceptable acid addition salt is a hydrochloride salt. 
     
     
         46 . The pharmaceutical composition of  claim 45  wherein said oral dosage form is a tablet or capsule. 
     
     
         47 . A method for the prevention or treatment of depression in a patient in need of said treatment comprising administering to said patient a composition containing polymorph form A of a pharmaceutically acceptable acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof and an inert carrier or diluent, said composition being administered in an effective amount to prevent or treat said depression. 
     
     
         48 . The method of  claim 47  wherein said pharmaceutically acceptable salt is the hydrochloride salt. 
     
     
         49 . The method of  claim 48  wherein said polymorph form A is administered to the patient at an oral dose of from about 0.5 mg/kg to about 5.0 mg/kg of body weight per day. 
     
     
         50 . A method for the prevention or treatment of depression in a patient in need of said treatment comprising administering to said patient a composition containing polymorph form B of a pharmaceutically acceptable acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline form substantially free of other geometric, optical and polymorphic isomers thereof and an inert carrier or diluent, said composition being administered in an effective amount to prevent or treat said depression. 
     
     
         51 . The method of  claim 50  wherein said pharmaceutically acceptable salt is the hydrochloride salt. 
     
     
         52 . The method of  claim 51  wherein said polymorph form B is administered to the patient at an oral dose of from about 0.5 mg/kg to about 5.0 mg/kg of body weight per day. 
     
     
         53 . A method for the prevention or treatment of depression in a patient in need of said treatment comprising administering to said patient a composition containing polymorph form C of a pharmaceutically acceptable acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in crystalline folio substantially free of other geometric, optical and polymorphic isomers thereof and an inert carrier or diluent, said composition being administered in an effective amount to prevent or treat said depression. 
     
     
         54 . The method of  claim 53  wherein said pharmaceutically acceptable salt is the hydrochloride salt. 
     
     
         55 . The method of  claim 54  wherein said polymorph form C is administered to the patient at an oral dose of from about 0.5 mg/kg to about 5.0 mg/kg of body weight per day 
     
     
         56 . A pharmaceutical composition comprising a mixture of polymorph form A and either or both polymorph form B and polymorph form C of a pharmaceutically acceptable acid addition salt of (+)-1-(3,4-dichloro)-3-azabicyclo[3.1.0]hexane. 
     
     
         57 . The pharmaceutical composition according to  claim 56  wherein the amount of polymorph form A ranges from about 10% to about 20% (by weight). 
     
     
         58 . The pharmaceutical composition according to  claim 56  wherein the amount of polymorph form A ranges from about 20% to about 35% (by weight). 
     
     
         59 . The pharmaceutical composition according to  claim 56  wherein the amount of polymorph form A ranges from about 35% to about 50% (by weight). 
     
     
         60 . The pharmaceutical composition according to  claim 56  wherein the amount of polymorph form A ranges from about 50% to about 70% (by weight). 
     
     
         61 . The pharmaceutical composition according to  claim 56  wherein the amount of polymorph form A ranges from about 70% to about 85% (by weight). 
     
     
         62 . The pharmaceutical composition according to  claim 56  wherein the amount of polymorph form A ranges from about 85% to about 95% (by weight). 
     
     
         63 . The pharmaceutical composition according to  claim 56  wherein the amount of polymorph form A ranges from about 95% to about 99% (by weight). 
     
     
         64 . A pharmaceutical composition comprising a mixture of polymorph form B and either or both polymorph form A and polymorph form C of a pharmaceutically acceptable acid addition salt of (+)-1-(3,4-dichloro)-3-azabicyclo[3.1.0]hexane. 
     
     
         65 . A pharmaceutical composition comprising a mixture of polymorph form C and either or both polymorph form A and polymorph form B of a pharmaceutically acceptable acid addition salt of (+)-1-(3,4-dichloro)-3-azabicyclo[3.1.0]hexane.